A retrospective cross-sectional study of FGFR2b alterations in Chinese patients with advanced squamous non-small cell lung cancer: prevalence, programmed death-ligand 1 co-expression patterns, and association with clinical outcomes

Introduction

The primary cause of cancer-related mortality worldwide is non-small cell lung cancer (NSCLC) (1,2). Squamous NSCLC (sqNSCLC) accounts for around 30% of NSCLC cases (2). Due to the lack of driver mutations, only a few somatically mutated inhibitor therapies could be used in sqNSCLC (3,4). However, targeted therapy for sqNSCLC is not very effective, and the overall objective response rate is less than 7% in previously treated sqNSCLC (5). Chemotherapy plus immunotherapy [immuno-oncology (IO)] has become a new standard of care for patients with previously untreated advanced sqNSCLC in recent years. Immunotherapy or chemotherapy are also recommended treatments for sqNSCLC patients (6). Although the combination of chemotherapy plus immunotherapy has improved the prognosis of patients with sqNSCLC, the median overall survival is still less than 3 years and new treatment options are needed (7-14).

Fibroblast growth factor receptor 2 (FGFR2) is one of four transmembrane receptors in the FGFR family that encode receptor tyrosine kinases (15,16). FGFR2 signaling has been found to be associated with tumor proliferation, migration, and angiogenesis (16). NSCLC is a tumor type with high frequency of FGFR2 single-nucleotide variants (SNVs), making them potential therapeutic targets (15,17). Unlike the broad amplicon structure of FGFR1, FGFR2 amplicons are narrow and generally centered on FGFR2, potentially resulting in better efficacy than targeting FGFR1 (18). FGFR2IIIb, also known as FGFR2b, is one of the isoforms of FGFR2 (19). FGFR2b is primarily expressed in normal epithelial cells, and in various tumor types such as gastric cancer, lung cancer, breast cancer, and esophageal cancer (19-22). FGFR2 amplification has been shown to be associated with poor prognosis in patients with gastric cancer (23).

FGFR2b-targeted therapy may be a new option for patients with sqNSCLC. An overexpression rate of FGFR2b protein (2+; and 3+ in any percentage of tumor cells) has been reported in more than 20% of stages IIIA-IVA sqNSCLC patients in Europe, South/North America, and Asia (24). FORTITUDE-201 (NCT05267470) is a study of bemarituzumab, a humanized IgG1 FGFR2b monoclonal antibody, as monotherapy and in combination with docetaxel for participants with sqNSCLC and FGFR2b overexpression. SCR-A002, developed by Simcere Zaiming, is a potential first-in-class FGFR2b-targeted antibody-drug conjugate (ADC) in the Investigational New Drug (IND)-enabling stage, which has shown promising efficacy and toxicity data in preclinical studies (25).

However, the expression of FGFR2b protein in Chinese advanced sqNSCLC patients is still unclear. To further evaluate FGFR2b-targeted agents as a new treatment option for Chinese advanced sqNSCLC patients, we conducted this retrospective, single-center, cross-sectional study in Chinese stage IIIB-IV sqNSCLC patients. Our aim was to explore the expression of FGFR2b protein, its overlap with programmed death-ligand 1 (PD-L1) expression levels, and its correlation with clinical characteristics and outcomes. We present this article in accordance with the REMARK reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-452/rc).

Methods

Participants

This is a retrospective cross-sectional study (ChiCTR2400090629). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Review Committee (ERC) of Peking University Cancer Hospital and Institute, China (Approval No. 2024KT42) and written informed consent for this retrospective analysis was waived. Three hundred newly diagnosed advanced sqNSCLC cases were identified over a six-year period (2018–2024). The study enrolled patients with histologically confirmed stage IIIB–IV sqNSCLC patients who had archival tumor tissue specimens collected from diagnosis until the initiation of first-line therapy. Demographic information (age, sex, and medical history), treatment information and efficacy were extracted from the Hospital Information System by well-trained research staff. To ensure data anonymization and privacy, data de-identification, access control and encryption, and data minimization and aggregation were taken in this study.

Tumor tissue collection and preparation

Diagnostic sqNSCLC tissue biopsies were collected from patients at Peking University Cancer Hospital and Institute between April 2018 and February 2024. The biopsies were fixed in 10% neutral-buffered formalin (NBF), embedded in paraffin, and stored. The archival tumor tissue specimens were serially sectioned at 4 µm, and dried at 60 ℃ for 1 hour.

FGFR2b immunohistochemistry (IHC) analysis

FGFR2b IHC testing was conducted on the Leica BOND III platform using the primary FGFR2b antibody provided by Simcere Zaiming. The antibody was diluted to a concentration of 12.29 µg/mL in antibody dilution (Cell Signaling Technology, 8112L). Antigen retrieval was performed using BondTM Epitope Retrieval Solution 1 (AR9961, pH 6.0) for 20 minutes at 100 °C. Tumor sections were incubated with the primary antibody at room temperature for 60 minutes, followed by incubation with Bond™ Polymer Refine Detection (DS9800) at room temperature for 8 minutes. Protein expression of FGFR2b was assessed based on membrane staining intensity (0, 1+, 2+, 3+) and percent staining (0–100%). Positive expression of FGFR2b was defined as any intensity of 1+, 2+, or 3+ in at least 1% of tumor cells. Overexpression of FGFR2b was defined as any intensity of 2+, 3+ in at least 1% of tumor cells.

PD-L1 IHC analysis

Historical PD-L1 IHC detection was performed on the Dako Autostainer Link 48 using the PD-L1 IHC 22C3 pharmDx kit (SK006). PD-L1 protein expression was evaluated using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Interpretation was done following the PD-L1 IHC 22C3 pharmDx Interpretation Manual for NSCLC. PD-L1 TPS ≥1% was considered positive expression, while PD-L1 TPS <1% was considered negative.

Statistical analysis

The sample size was based on the feasibility of accessing newly diagnosed cases within the specified timeframe rather than a prospective statistical power calculation. Eligible participants’ clinical characteristics were descriptively summarized by the expression of FGFR2b protein and the PD-L1 expression levels. Continuous variables were expressed as mean [standard deviation (SD)], median and interquartile range (IQR). Categorical variables were expressed as numbers and percentages.

The number and percentage of patients with valid FGFR2b results were summarized according to the expression status. The χ² test was employed to evaluate the co-expression of baseline FGFR2b and PD-L1 in patients who had valid protein expression data for both FGFR2b and PD-L1. Additionally, the Cochran-Mantel-Haenszel (CMH) test for general association was conducted, adjusting for age (<65 vs. ≥65 years) and histologically confirmed disease stages (III vs. IV) as stratification variables.

The overall response rate (ORR) and disease control rate (DCR) were defined based on the best overall response for patients who had valid baseline and post-baseline assessments by the investigator according to RECIST v1.1. ORR and DCR were estimated separately in paclitaxel/nab-paclitaxel (PTX) plus platinum (P) with or without anti-PD-1/PD-L1 antibodies treatment groups and by FGFR2b protein expression status. The corresponding 2-sided 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method.

Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 was defined as the time from the start of treatment to the first documented event (disease progression or death). For patients without a documented event, PFS was censored at the date of the last tumor assessment. Kaplan-Meier curves were produced and a log-rank test was conducted to compare the difference between treatment groups of PTX plus P with or without anti-PD-1/PD-L1 antibodies.

Statistical analyses were performed using R, version 4.4.2 (R Project for Statistical Computing), with a 2-sided α =0.05 indicating statistical significance.

Results

Participant characteristics

A total of 266 advanced sqNSCLC patients with valid FGFR2b protein expression status were enrolled in this cross-sectional study. Of these, 238 were male patients (89.5%) and 28 were female patients (10.5%). The median age was 65 (IQR, 59.0–70.0) years. Among the participants, 117 patients (44.0%, 117/266) were diagnosed with IIIB/IIIC-stage cancer, with 70 being FGFR2b-positive and 47 being FGFR2b-negative. Additionally, 149 patients were diagnosed with IV-stage cancer, with 65 being FGFR2b-positive and 84 being FGFR2b-negative.

Of the 266 patients, 164 had smoking status information available, with 143 having a smoking history and 21 not having a smoking history. The smoking history of 102 patients was unknown. Furthermore, 204 patients had a valid PD-L1 protein expression status. Out of these, 108 patients received treatment with PTX plus P with or without anti-PD-1/PD-L1 antibodies, and 104 of them had response data available. Additionally, 158 patients were treated with other chemotherapies with or without anti-PD-1/PD-L1 antibodies. Please refer to Figure 1 for the study flow chart, Table 1 for participant characteristics.

Figure 1 Disposition of participants in the study. FFPE, formalin-fixed paraffin-embedded; FGFR2b, fibroblast growth factor receptor 2b; IHC, immunohistochemistry; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PTX + P, paclitaxel or nab-paclitaxel + platinum; sqNSCLC, squamous non-small cell lung cancer.

FGFR2b protein expression in advanced sqNSCLC

Among the 266 patients with valid FGFR2b protein expression status, 135 (50.8%) were identified as FGFR2b-positive expression, 52 (19.5%) as FGFR2b overexpression, and 131 (48.2%) as FGFR2b-negative. The proportion of male patients was higher in the FGFR2b-positive population than in the FGFR2b-negative population [93.3% (126/135) versus 85.5% (112/131), P=0.04], and the proportion of patients with IIIB/IIIC-stage cancer was higher in the FGFR2b-positive population than in the FGFR2b-negative population [51.9% (70/135) versus 35.9% (47/131), P=0.01]. Please refer to Figure 2 for FGFR2b staining intensity of 0, 1+, 2+, and 3+.

Figure 2 FGFR2b IHC staining in sqNSCLC (40× magnification). (A) Representative image of FGFR2b-negative; (B) representative image of FGFR2b weak intensity: 1+; (C) representative image of FGFR2b moderate intensity: 2+; (D) representative image of FGFR2b strong intensity: 3+. FGFR2b, fibroblast growth factor receptor 2b; IHC, immunohistochemistry; sqNSCLC, squamous non-small cell lung cancer.

Overlap of FGFR2b protein expression with PD-L1 protein expression

Out of 204 patients, valid FGFR2b and PD-L1 protein expression statuses were available. Among them, 111 (54.4%, 111/204) were identified as FGFR2b-positive expression, 44 (21.6%, 44/204) as FGFR2b overexpression, and 93 (45.6%, 93/204) as FGFR2b-negative. Additionally, 54 (26.5%, 54/204) had PD-L1 TPS ≥50%, 98 (48%, 98/204) had PD-L1 50%> TPS ≥1%, and 52 (25.5%, 52/204) had PD-L1 TPS <1% (Table 2). The median age of patients with PD-L1 TPS ≥50% was younger than those with PD-L1 TPS <1% [median (IQR) age, 64 (58.2–67.8) years versus median (IQR) age, 68 (61.0–72.0) years, P=0.05], and the proportion of patients with a smoking history was higher in the PD-L1 TPS <1% population than in the PD-L1 TPS ≥50% population (P=0.04) (Table 3). FGFR2b and PD-L1 were co-expressed in 81.1% (90/111) of the FGFR2b-positive expression population, and 86.4% (38/44) of the FGFR2b-overexpression population (Figure 3, Table 2).

Figure 3 Co-expression of FGFR2b and PD-L1. Among 266 Chinese patients with stages IIIB-IV sqNSCLC, FGFR2b-positive rate was observed in 54.4% of cases, while negativity was demonstrated in 45.6%. In the FGFR2b-positive group, PD-L1 TPS ≥50% was observed in 30% of individuals, 50%> TPS ≥1% in 51%, and TPS <1% in 19%. In the FGFR2b-negative group, PD-L1 TPS ≥50% was observed in 23% of individuals, 50%> TPS ≥1% in 44%, and TPS <1% in 33%. FGFR2b, fibroblast growth factor receptor 2b; PD-L1, programmed death-ligand 1; sqNSCLC, squamous non-small cell lung cancer; TPS, tumor proportion score.

Correlation of baseline FGFR2b protein expression with overall response and PFS

One hundred and eight patients were treated with PTX plus P with or without anti-PD-1/PD-L1 antibodies, with 27 receiving PTX plus P and 81 receiving PTX plus P with anti-PD-1/PD-L1 antibodies.

In both the PTX plus P with and without anti-PD-1/PD-L1 antibodies treatment groups, overall response (complete response/partial response) was more frequently observed in the FGFR2b-positive population [27 (57.4%, 27/47) and 3 (27.3%, 3/11), respectively], compared to the FGFR2b-negative population [13 (41.9%, 13/31) and 1 (6.7%, 1/15), respectively] (Table 4). Disease control rates of both treatment groups were quite comparable, regardless of the expression of FGFR2b (Table 4).

The median PFS (mPFS) for patients who received PTX plus P was 9.0 months (95% CI: 7.0–NA), with no significant difference between FGFR2b-positive and negative populations (Figure 4, Table 5). The mPFS for patients who received PTX plus P with anti-PD-1/PD-L1 antibodies was 10.8 months (95% CI: 6.2–15.0). Comparatively, patients with FGFR2b-negative expression had a numerically shorter mPFS than those with positive expression [11.3 (95% CI: 6.6–17.9) vs. 6.5 (95% CI: 5.5–17.3) months] (Figure 4, Table 5).

Figure 4 Correlation of baseline FGFR2b protein expression with PFS. (A) PFS of paclitaxel or nab-paclitaxel + platinum + PD-1/PD-L1 antibodies, FGFR2b-negative vs. FGFR2b-positive expression; (B) PFS of paclitaxel or nab-paclitaxel + platinum, FGFR2b-negative vs. FGFR2b-positive expression. FGFR2b, fibroblast growth factor receptor 2 b; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PFS, progression free survival.

Discussion

To date, this study features the only published FGFR2b prevalence data in the Chinese advanced sqNSCLC population. It is also the first study to demonstrate the association of FGFR2b protein expression with the clinical characteristics of advanced sqNSCLC patients and the clinical outcomes of the first-line treatment of paclitaxel or nab-paclitaxel plus platinum with or without anti-PD-1/PD-L1 antibodies.

FGFR2b may become a potential therapeutic target for patients with advanced sqNSCLC, similar to its excellent role in the targeted therapy of gastric cancer (26-28). Our results demonstrate that over 50% of sqNSCLC tissue specimens positively express FGFR2b (Table 2). It also confirms the prior report presented by Dr. Akamatsu and his team that FGFR2b protein is overexpressed in over 20% of 250 sqNSCLC specimens from stage IIIA to stage IVA (24). Although their study included samples from 51 patients from Hong Kong SAR, the study population was not specifically targeted at patients with advanced sqNSCLC since 55 patients with stage IIIA sqNSCLC were also enrolled. Different IHC staining platforms were used in the two studies. Our Leica anti-FGFR2b assay is comparable to the Ventana anti-FGFR2b clone FPR2D assay used by their study in terms of staining pattern and intensity (Figure 2). Correlation analysis of FGFR2b expression with clinical characteristics has been performed (Table 1). The FGFR2b-positive rate is higher in males than in females, which may be due to the limited sample size in females. We didn’t observe any difference in FGFR2b expression between smoking and non-smoking groups. A significant correlation between FGFR2b expression and cancer stage was observed (P=0.01). The FGFR2b-positive rate was much higher in stage IIIB/IIIC, compared to stage IV. Since no relevant data has been reported before, further validation will be performed in the future.

High co-expression of FGFR2b and PD-L1 in advanced sqNSCLC indicates the high potential of combining FGFR2b-targeted agents with anti-PD-1/PD-L1 antibodies. Our results (Table 2) of over 80% co-expression of FGFR2b and PD-L1 in FGFR2b either positive or overexpression populations suggest that FGFR2b could be a predictive marker in the selection of patients for the combination of FGFR2b-targeted agents with anti-PD-1/PD-L1 antibodies regardless of PD-L1 expression status. A high overlap of FGFR2b and PD-L1 data was also reported by Dr. Akamatsu and his team (24), though it’s lower than ours, which might be due to the randomness of cancer stages, races, and PD-L1 expression in a limited sample size. In the Chinese population of advanced sqNSCLC, the proportion of PD-L1 (22C3) positive expression has been reported in approximately 60% (29), which is comparable to our results (Table 2). A phase 1b/3 study of bemarituzumab + mFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102) has been initiated (30). Similarly, FGFR2b-targeted agents in combination with anti-PD-1/PD-L1 antibodies may also have potential clinical development prospects in advanced sqNSCLC.

It has been reported that FGFR2 IIIb (FGFR2b) expression correlated with the well-differentiated cell type of esophageal cancer, and tended to correlate with a good prognosis in gastric cancer (31,32); however, it’s still unclear in NSCLC. In our study, the mPFS regardless of FGFR2b expression is 10.8 months (95% CI: 6.2–15.0) in patients who received PTX + P + anti-PD-1/PD-L1 antibodies (Table 5), which is comparable with previous registrational trials of chemotherapy plus anti-PD-1/PD-L1 antibodies in advanced sqNSCLC, including RATIONALE-307, KEYNOTE-407, and Impower131 (13,33,34). Different from tumor mutation burden (TMB) status and PD-L1 expression that do not correlate with the efficacy of chemotherapy plus anti-PD-1/PD-L1 antibodies in sqNSCLC (35,36), our study suggests that FGFR2b expression may associate with a good clinical outcome, in which mPFS is numerically longer in the FGFR2b-positive group [11.3 months (95% CI: 6.6–17.9)] compared with the FGFR2b-negative group [6.5 months (95% CI: 5.0–17.3)]. Although the same trend was observed in the ORR of PTX + P with or without anti-PD-1/PD-L1 antibodies, it was particularly interesting that no correlation was found between FGFR2b expression and PFS of PTX + P treatment. This may be due to immature PFS because of an insufficient number of events (Table 5).

To our knowledge, this is the first study on FGFR2b prevalence in Chinese patients with advanced sqNSCLC. All archival tumor tissue specimens were collected between diagnosis and first-line therapy. This study holds significant value for the development of FGFR2b-targeted therapies in patients with advanced sqNSCLC.

However, there are several limitations in this study. Firstly, although males are predominant in sqNSCLC patients, the number of female patients in this study is too small to be representative. Secondly, not all enrolled patients have valid historical PD-L1 data and smoking history data. Thirdly, not all patients received PTX + P as a first-line chemotherapy agent, resulting in a small sample size for the PTX + P group with or without anti-PD-1/PD-L1 antibodies. Fourthly, the follow-up time was not long enough and overall survival data were not available. Further research will be required, particularly in historical data extraction and mining, extending patient follow-up time, and exploring the potential molecular mechanisms driving the co-expression of FGFR2b and PD-L1. In addition, further studies with a new cohort are needed to address that the very low proportion of female patients in this study may limit the generalizability of certain findings in this subgroup.

Conclusions

In this cross-sectional study of 266 advanced sqNSCLC patients, it showed an over 50% FGFR2b-positive expression rate, high co-expression of FGFR2b and PD-L1, and a correlation between FGFR2b expression and clinical characteristics and outcomes. These results support the use of the FGFR2b protein as a predictive marker for developing FGFR2b-targeted therapies in sqNSCLC and the feasibility of combining FGFR2b-targeted therapies and anti-PD-1/PD-L1 antibodies as first-line or later-line treatments for this population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-452/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-452/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-452/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-452/coif). X.W., S.S., C.A., J.L., Y.G., C.Y., Y.F., and R.T. are from Simcere Zaiming Pharmaceutical Co., Ltd. (a for-profit company). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Review Committee (ERC) of Peking University Cancer Hospital and Institute, China (Approval No. 2024KT42) and written informed consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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